Dioxatricyclodecanes

ABSTRACT

A 2,9-DIOXATRICYCLO-(4,3,1,0,3,7)-DECANE OF THE FORMULEA IA AND IB   3-(R2-CH2-),4-(R3-O-),8-R1,10-(CH2=)-2,9-DIOXATRICYCLO-   (4.3.1.0(3,7))DECANE AND   3-(R2-CH2-),8-R1,10-(CH2=)-2,9-DIOXATRICYCLO-   (4.3.1.0(3,7))DECAN-4-ONE   IN WHICH R1 IS ALKOXY OR ARALKOXY, R2 IS HYDROGEN, HALOGEN OR -SCN, R3 IS HYDROGEN OR ACYL, AND THE 10, 11DOUBLE BOND MAY ALSO BE HYDROGENATED. THE COMPOUNDS ARE HYPOTENSIVE AND CENTRALLY DEPRESSANT AND ANALGETIC AGENTS AND ARE USEFUL FOR TREATING ARTERIOSCLEROTIC DISEASES AND AS PSYCHOPHARMACEUTICALS.

May 4211, 1974 P. W. THIES DIOXATRI oYcLoDEcANEs 3 Sheets-Sheet 2 FiledDec. 7. 1970 N GE,

INVENTOR l//amfaaap Til/f5 BY 1f/W L ATTORNEY 3 Sheets-Sheet :5

Filed Dec. '7. 1970 mwN m. .mi Sm mmx 35 QQQ . w w .2. .uw

ATTORNEY -'United States Patent Oce 3,812,154 Patented May 21, 1974 U.S.Cl. 260-340.3 3 Claims ABSTRACT OF THE DISCLOSURE A2,9-dioxatricyclo-(4,3,l,0,3")decane of the formulae Ia and Ib in whichR1 is alkoxy or aralkoxy, R2 is hydrogen, halogen or SCN, R3 is hydrogenor acyl, and the 10,11- double bond may also be hydrogenated.

The compounds are hypotensive and centrally depressant and analgeticagents and are useful for treating arteriosclerotic diseases and aspsychopharmaceuticals.

SUMMARY OF THE INVENTION The invention resides in a bridge-linked ringsystem 2,9-dioxatricyclo(4,3,1,0,3")decane of the formulae Ia and Ib inwhich R1 is alkoxy or aralkoxy, R2 is hydrogen, halogen or -SCN, R3 ishydrogen or acyl, and the 10,11- double bond may also be hydrogenated.

The compounds are hypotensive and centrally depressant and analgeticagents and are useful for treating arteriosclerotic diseases and aspsyehopharmaceuticals.

The invention also embraces a process for making the above compounds.For instance the compounds may be made by reacting a cyclopenta(c)-pyran of the formula II with an alcohol in an acid medium, X in theabove formula being a group that can be eliminated during the reactionsuch as an acyloxy radical, R1 being acyloxy or a -D-glucosido group, R2being halogen, hydrogen or -SCN and R3 being hydrogen or acyl.

The reaction preferably is carried out at -80 C.

The novel features which are considered as characteristic for theinvention are set fo-rth in particular in the appended claims. Theinvention itself, however, both as 5 to its construction and its methodof operation, together with additional objects and advantages thereof,will be best understood from the following description of specificembodiments when read in connection with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS FIGS. l, 2 and 3 are infrared spectraof the compounds obtained in Examples 3, 5 and 6, respectively.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The compounds of the inventionare pharmaceutically important compounds which were discovered in thecourse of psychopharmacological and analytical blood research studies.

yPreferably in the above formulae alkyl or alkoxy has 1 to 4 and acyl oracyloxy has 1 to 6 C atoms.

The synthesis of these compounds can proceed from cyclopenta(c)pyrans ofthe general formula II wherein X is a group that can be eliminated, suchas an acyloxy radical, preferably derived from acetic, iso valerie oriso caproic acid, R1 is an acyloxy radical or a -D-glucosido group, R2is a halogen atom a hydrogen atom or an -SCN radical and R3 is ahydrogen atom or an acyl radical. Necessary conditions for cyclizationwhich can be performed in an acid, preferably an alcoholic medium, arefirstly the cisoid position of the C-7 hydroxyl group and of the pyranring on the cyclopentane ring and secondly the presence of the reactiveallyl system at the C-atoms numbered Cf-3, C-4 and C-8. Cyclizationconsists in the creation of a link between the hydroxyl oxygen at the C7atom and the 0 3 atom with the simultaneous rearrangement of the allylsystem and the elimination of HX. Since the reaction is performed in thepresence of an alcohol and in the presence of an acid catalyst, such ashydrochloric acid p-toluenesulphonic acid or a Lewis acid, thereplacement of the R1 group at the C-l atom by an alkoxy or aralkoxyradical corresponding to the alcohol used can be effected byalcoholysis.

Compounds of formula II, wherein R1 is an acyloxy radical and R2 is ahalogen atom or an SCN, can be obtained from the didrovaltratum and itshomologues and conversion of the epoxides into corresponding hydrins. Inmany cases it is possible to use the raw extracts of the substances assuch for the preparation of the 2,9-dioxatricyclo-(4,3,1,0,3f7)decane.

The compounds of the above noted formula Ia, which result from thisreaction are generally colourless, distillable oils or wellcrystallizable compounds of surprising stability. They are usuallysoluble in water and can be modified chemically. For instance, anacyloxy radical at the C-4 atom can be hydrolysed to the hydroxy groupand at the same time a holomethyl radical at the C-3 atom can becatalytically reduced to a methyl, leading compounds of the followingformula III Compounds of formula III can also be obtained from thel--D-glucosido4-isovaleroxymethyl-6,7-dihydroxy-7- methyl-1,4a,5,6,7,7ahexahydrocyclopenta(c)pyran of the following formula IIa This glucosideis obtained by extraction of roots and rhizomes of Valeriana specieswith a polar solvent such as water, alcohol, acetone, ethyl acetate or amixture of two or more thereof or a mixture of a halogenated hydrocarbonand an alcohol and by isolating the glucoside from the extract forinstance by chromatography on silica gel or alumina using ethyl acetatewith an addition of an alcohol. For the synthesis of the2,9-dioxatricyclo(4,3, 1,0,3'7)decane of formula III the ester glucosideof formula IIa is reacted with an alcohol in the presence of a strongacid such as hydrohalic acid, a sulphonic acid or a Lewis acid. Howeverit is not in all cases necessary to isolate the glucoside from theextract, but it is possible to use the raw extract as such for thesynthesis. These compounds of formula III have an unmistakable centraldepressant effect on mice when administered per os in doses notexceeding 31.6 to 100 mg./kg. The LD50 is at 600 to 2500 mg./kg. per s.This provides a very useful therapeutic range for the use of thesesubstances.

Moreover, in compounds of the formula III the double bond between theC10 and C-11 carbon atoms can be hydrogenated in conventional manner toprovide compounds of the following formula IIIa.

( A ralKy) o-Alltyl The same compounds can also be directly obtainedfrom substances of formula la in which Rl is an alkoxy or aralkoxyradical, R2 is a halogen atom and R3 is an acyl radical, bycatalytically hydrogenating the compound in an alcohol and in thepresence of a strong base, such as caustic soda or caustic potash, thepreferred catalyst being Raney nickel.

After peroral administration in doses that are only fractions of theLD50, these compounds have a surprisingly powerful dilating effect onarterial vessels and they are hypotensive and centrally depressantwithout reducing reflex excitability, contrary to, for instance,reserpine, which has a hypotensive eiect but also reduces reflexexcitability as an undesirable side effect.

The present substances can therefore be used for treatingarteriosclerotic diseases and as a psychopharmaceutical. Thisconstitutes a considerable step forward in the therapeutic art andparticularly in geriatrics.

The alcohol group attached to the C4 atom can be converted into a ketogroup by oxidation of compounds of the above formulae III and IIIa.There are thus formed the corresponding2,9-dioxatricyclo-(4,3,1,0,3f7)decanone of the formula Ib The productionof 4-acetoxy-3-halomethyl-(orthiocyanomethyl)-10-methylene-S-methoxy-Z,9dioxatricyclo-(4,3,l,0,3'7)decanewherein X=I, SCN, Br or C1.

For the production of the 3-iodomethyl compound 6- acetoxy 1,4a,5,6,7,7ahexahydro 1 (isovaleroxy) 4- (isovaleroxymethyl) cyclopenta (c) pyran 7spiro 2- oxirane (didrovaltratum) ococ Mac lc nata. (cnicucnacoocua clla! are dissolved in 25 ml. of methanol and then treated with a furtherl0 m1. of methanol containing 19 g. of HCl in solution, whilstexternally cooling with ice. Gradually the solution assu-mes a darkgreenish-blue colour. After having been allowed to stand for an hour atroom temperature, it is diluted with water, exhaustively extracted withdiethyl ether and the ether phase is neutralized with sodiumbicarbonate. After drying over sodium sulphate, clarifying with a littlecharcoal and concentrating in a vacuum (at 7 mm. Hg and 50 C.) until theweight remains constant or until the odour of the methyl isovaleratedisappears, 13.8 g. of a pale brown oil are obtained which, after havingbeen taken up in a little methano1/ether slowly crystallizes when keptstanding in the cold.

The resultant 4-acetoxy-3-iodomethyl-10methylene8.methoxy-Z,9-dioxatricyclo-(4,3,1,0,3'1)decane crystallizes in the formof white prisms and has the following characteristic physical data:

ClaHitOsI M01. Wt.: 330.19 MP: 104l06 C. [alum-468 (in methanol) Fromthe corresponding didrovaltratum halohydrins prepared fromdidrovaltratum and sodium bromide or sodium chloride the followingcompounds were successfully prepared in analogous manner:

Mol. wt.: 333.2 MP: lOl-102 C. []D2u=..|.80 (in methanol) Ifdidrovaltratum is reacted with potassium thiocyanide in aceticacid/sodium acetate, then didrovaltratum thiocyanohydrin, will formwhich can be cyclized by an analogous treatment` with HCl in methanol toform 4- acetoxy-3thiocyanmethyl10-methylene-8-methoxy 2,9-dioxatricyclo-(4,3,1,0,3-")decane that has the following characteristicphysical data:

CuHuOsNS M01. Wt. 311.34

MP: 11S-120 C. [a]D2o=+46 (in methanol).

If the methanol is replaced by a different alcohol, such as ethanol,propanol, butanol or benzyl alcohol, the corresponding 4-acetoxy-3halomethyl-10-methylene-8-alkoxy- (or aralkoxy)2,9-dioxatricyclo-(4,3,1,0,3-'1)decanes are obtained.

' EXAMPLE 2 The production of Alky1=CH3.

A solution of 0.7 g. of 4 acetoxy-3-iodomethyl-10- methylene 8 methoxy2,9 dioxatricyclo (4,3,1,0,3'7) decane, prepared as described in Example1, in 20 ml. of methanol containing 0.5 ml. of diethylamine, is added toa suspension of 0.08 g. of Raney nickel in 20 ml. of methanol, and themixture is hydrogenated by shaking at room temperature and atmosphericpressure with hydrogen. In the course of minutes, one equivalent ofhydrogen is consumed. After filtration through asbestos, the filtrate isconcentrated until dry and the residue is extracted with chloroform.

After having been washed with water, dried over magnesium sulphate andconcentrated in vacuo (at 7 mm. Hg at 50 C.), the chloroform extractyields 0.426 g. of 4- acetoxy-3-methyl-10-methylene-8-methoxy 2,9dioxatricyclo-(4,3,1,0,3-")decane in the form of a colorless oil, i.e.90.5% of theory.

The oil is then dissolved in 25 ml. of methanol and 5 ml. of a 1N-solution of caustic soda are added to the solution. After having beenallowed to stand for one hour at room temperature, the solution isdiluted with water and extracted with ethyl acetate. After the ethylacetate phase has been neutralized, dried over magnesium sulphate andconcentrated in a vacuum (at 7 rnrn. Hg and 50 C.) it yields 0.292 g. of4-hydroxy-'3-methyl-10-methylene 8methoxy-2,9-dioxatricyclo(4,3,1,0,3'7)-decane as a colorless oil:

:inw-:1.5096

EXAMPLE 3 The production of 4hydroxy-3,10-dmethyl-8-methoxy-2,9-dioxatricyclo-(4,

3,l,0,3"') decane from 4 acetoxy-S-iodomethyl-IO- methylene 8methoxy-2,9dioxatricyclo(4,3,1,0,3-7) decane 3.8 g. of4-acetoxy-3-iodomethyl-10-methylene-S-methoxy-2,9dioxatricyclo(4,3,1,055.7)-decaneare dissolved in 25 ml. of methanol which contains 0.85 g. of sodiumhydroxide.

About 0.4 g. of Raney nickel moistened with methanol are suspended in 20ml. of methanol and filled into a hydrogenating bulb. As soon as thecatalyst is saturated with hydrogen, the solution of the substance isadded to the catalyst suspension and hydrogenated with hydrogen understandard conditions (room temperature and 760 mm. Hg). In the course of45 minutes, a total of 450 ml. of hydrogen are taken up.

The mixture is then filtered through asbestos and the filtrateconcentrated in a vacuum (at 7 mm. Hg and 50 C.) until its weightremains constant. After having been taken up in water and salted outwith ammonium sulphate, the solution is extracted with ether. The etherphase is dried over` magnesium sulphate, filtered and concentrated untildry. 1.6825 g. of 4-hydroxy-3,IO-dimethyl-S- methoxy2,9-dioxatricyclo-(4,3,1,0,37)decane are obtained in the form of acolorless highly viscous oil, representing 78.9% of the theory.

Mol. wt.: 214.26 [a]D21=-12 (in methanol) The compound is readilysoluble in ether, alcohol and up to 2% in water. The IR-spectrum isreproduced in the accompanying drawing, FIG. 3.

If the starting substance is a compound which is substituted in the8position with an ethoxy, propoxy or butoxy group then the correspondingalkoxy compound is obtained.

EXAMPLE 4 7-methyl-1,4a,5,6,7,7a-hexahydro-cyclopenta(c) pyran.

The 1 D-glucosido-4-isovaleroxy-methyl-6,7dihy droxy 7methyl-1,4a,5,6,7,7a-hexahydro-cycl0penta(c) pyran is obtained asfollows:

6 kg. of ground roots and rhizomes of Valeriana wallchi were firstexhaustively percolated in a percolator with n-hexane and a 1% additionof acetic acid. This first percolate was discarded. A second percolationwas then carried out with chloroform and methanol in the proportion of:2. The slightly concentrated percolate was washed three times, eachtime with 10 litres of water. The organic phase was discarded and theaqueous phase, hav ing been saturated with ammonium sulphate, wasextracted four times, each time with 5 litres of ethyl acetate. Theester phase was dried over magnesium sulphate and concentrated untildry. The total residue was 199 g., i.e. 3.31% related to the dried drug.

The fraction which primarily consisted of water-soluble ester glucosideswas subjected to columnar chromatography for further purification:

10 g. of ethyl acetate residue were taken up in about 100 ml. of dampethyl acetate and, after having been allowed to stand for a while, anyinsoluble substances was filtered off. The ltrate was applied to asilicon gel column that had been filled with 250 g. of gel-grain size0.2 to 0.5 mm. The suspension of the silica gel and the first elutionwere done with moist ethyl acetate, but later elution was continued withethyl acetate containing an addition of methanol. Fractions of 100 ml.were collected. The

`compound according to the invention, namely1--D-glucosido-4-isovaleroxymethyl-6,7-dihydroxy-7-methyl-1,4a,5,6,7,7a-hexahydrocyclopenta(c)pyran was present in the fractionsnumbered 17 to 27. From these fractions, after concentration, a total of3, 65 g. of the glucoside were isolated in the form of an amorphousyellowish powder.

1 g. -D-glucosido-4-isovaleroxymethyl6,7-dihydroxy-7-methyl1,4a,5,6,7,7a hexahydro cyclopenta(c)pyran was dissolved in 20ml. of an alkanol and 50 mg. of ptoluenesulphonic acid were added to thesolution. After briefly heating to 40 C., 60 ml. of diluting water wereadded, the solution was neutralized with sodium bicarbonate andextracted with ethyl acetate. The entire extract was dried over sodiumsulphate. After concentration in a vacuum, light brown oils wereobtained which were purified by preparative thick layer chromatographyon silica gel plates, the washing mixture consisting of 24 parts ofethyl acetate, 60 parts of n-hexane and 6 parts of n-propanol. (Largerquantities were purified by column chromatography on alumina withdiethyl ether as the eluent or by vacuum distillation.)

According to the alkanol used, the following compounds were produced:

1. lUsing methanol:

4-hydroxy-3-methyl-IO-methylene 8 methoxy 2,9- dioxatricyclo- (4,3,1,0,3"1)decane.

Mol. wt: 212.25 [a.]D2: +42u (in methanol) nD20: 1.5096

2. Using ethanol: 4-hydroxy-3-methyl-10 methylene 8 ethoxy 2,9-dioxatricyclo- (4,3 ,1,0,3") -decane.

C12H1s04 Mol. wt.: 226.28 [1111,20: +55 (in water) 111,20: 1.4983

3. Using n-butanol: 4-hydroXy-3-methyl-lO-methylene-S-(n butoxy) 2,9-dioxatricyclo(4,3,1,0,37) -decane.

Mol. wt.: 254.33 [001320: +39 (in methanol) "D20: 1.4908

The substances obtained have a clearly marked central depressant effectwhen administered to mice per os in quantities as small as 31.6-100mg./kg. These effective doses are only about 1,420 of the measured LD50.

IBy simple hydrogenation with palladium/active carbon, these compoundsyield the corresponding 4hydroxy 3,10dimethyl-8-alkoxy-2,9 dioxatricyclo(4,3,l,0,3") decanes that are hydrogenated in the 10, 11 positions.

EXAMPLE 5 4.2 g. of 4-hydroxy-3-methyl-10-methylene-'8-methoxy-2,9-dioxatricyclo-(4,3,l,0,37)-decane were dissolved in 100 ml. acetoneand reacted with 30 ml. of a chromium trioxide solution while coolingthe reaction mass. The chromium trioxide solution was formed as follows:

2.67 g. CrO3 (chromium trioxide) were dissolved in l0 ml. concentratedH2504 and the solution was cautiously poured into 30 ml. water and thenbrought up to a total volume of 50 ml. by adding further amounts ofwater.

A few minutes after adding the chromium trioxide compound the mass waspoured into ice water and extracted with chloroform. After drying of thechloroform phase over sodium sulfate and concentration in vacuo, therewere obtained 3.2 g. of 3methyl10methylene8methoxy-2,9dioxatricyclo(4,3,1,0,3") decane 4 one (compound 5 of thetable reproduced below). 'Ihis was a yield of 77% of the theoreticalyield.

vtAfter recrystallization from methanol there were obtained whitecompact crystals having the following physical characteristics Empiricalformula C11H14O4.

Molecular weight 210.23.

Melting point 8688 C.

Optical rotation [00920: +23 in methanol IR-spectrum Characteristic v-COabsorption peaks at 1745 cm.'1 (in KBr) as shown in FIG. 2. Solubility:Highly soluble in alcohol,

acetone, ether, chloroform acetic acid ester and about at 2% in water.

EXAMPLE `is 9.6 g. of 4hydroxy3,10dimethyl 8 methoxy 2,9-dioxatricyclo-(4,3,1,O,3")decane were dissolved in 300 ml. acetone andwere oxidized by slow addition of the chromium trioxide solutiondescribed in Example 5. The

reaction was carried out at room temperature while stirring. When it wascomplete the orange-brown color of the reagent no longer disappeared.The mass was then immediately poured into 700 ml. ice water and theaqueous/alcoholic solution was extracted with chloroform. After dryingof the chloroform phase over sodium sulfate and concentration in vacuothere -were obtained 9.5 g. 3,10-dimethyl-8-methoxy 2,9 dioxatricyclo(4,3,l, 0,3"i)decane4one in crystalline form (compound 6 of the tablebelow). This was a yield of 100% of the theoretical yield.

After recrystallization from 75% ethanol there were obtained 7.8 g. of amaterial which proved entirely pure in analysis. The material was in theform of compact white crystals of the following characteristics:

Empirical formula C11H10O4.

Molecular Weight 212.25.

Melting point 107-109 C.

Optical rotation [04,020: 56 in methanol.

IR-spectrum Characteristic v-CO absorption peaks at 1753 cm.1\(in KBr)Vsee FIG. 3.

Solubility Highly soluble in alcohol,

acetic acid ester, chloroform, acetone and at about 2% in i water.

EXAMPLES 7-10 Additional 2,9-dioxatricyclo-(4,3,1,0,3") decane 4- onecompounds were obtained by oxidation of the corresponding2,9dioxatricyclo (4,3,1,0,3G) decanols with chromium trioxide solutionas described in Examples 5 and 6. In the following tables the compoundsof Examples S and 6 together with these additional compounds areidentified and their properties are listed.

(D20 MeOH, Empirical Ex. Ri Rz deg. M.P.,C. formula.

CH! H +25 8688 CUHMOA 6----. 10,11-p0Si- CH: H -56 107-108 CnHiuOa tionhydrogen- 7 -410---" 02H5 H 50 61-62 ClzHlgO --dO--..-- 04H0 H -56 42-43C14H22O4 -.d0.- CHzCeHs H -77 77-79 (3i-:H2004 60----- CH; C1 -48 01CuHisOiCl l A pharmaceutical composition incorporating the compounds ofthe invention as the active ingredients can be formed in conventionalmanner by using conventional carrier materials which are inert to theactive components. The carrier materials may, for instance, be water, apharmaceutically acceptable vegetable oil, gelatin, lactose, apolyethyleneglycol, starch, magnesium stearate, talcum, etc.

F or the parenteral application solutions, preferably oily or aqueoussolutions may best be used. However, the compounds can also be appliedin suspensions or emulsions.

For the enteral application, tablets, capsules or lozenges may be usedwhichmay contain the usual additives, for instance preservatives,stabilizers or wetting agents. The compounds may be applied by mouth orby subcutaneous or intravenous injection. For human patients, thepreferred single dose for application per os is between 10 and 100 mg.In the case of animals, the dose may be higher.

The LD50 determined by application by mouth to white mice as testmaterials was 600 to 2500 mg./kg. 0f particular interest is that thei.v. toxicity of the water-soluble compounds in the case of the whitemice was found to be at an LD50 of 500 ing/kg.

Regarding the hypotensive action, this was determined by noting thedilation of the arterial vessels and the consequent increase of theperipheral ow in tests with cats and dogs. For instance, withnonanaesthetized dogs, a clearly noticeable lowering of the bloodpressure occurred already at a dose of 21.5 mg./kg. administered per os.The lowering of the blood pressure developed during the first hour andpersisted for several hours.

The central depressant effect has been established by the fact that asubstantial lengthening of the evipan anaesthesia occurred afteradministration of the cornpounds.

In experiments With white mice in a dosage of 31.6 mg./kg. per os of thecompound of Example 6 above, a marked lowering of the spontaneousactivity was found to prevail for a time up to one hour afterapplication of the drug. The LD50 in this case was found to be 2150mg./kg.

The same dose which caused reduction of the activity produced ananalgesic effect (Writhing Test), which was stronger than that of mg.acetyl salicyclic acid. Similar observations were obtained with thecompounds of Examples 7 and 8.

Without further analysis, the foregoing will so fully reveal the gist ofthe present invention that others can, by applying current knowledge,readily adapt it for various applications without omitting featuresthat, from the standpoint of prior art, fairly constitute essentialcharacteristics of the generic or specific aspects of this invention.

What is claimed as new and desired to be protected by Letters Patent isset forth in the appended claims:

1. A 2,9-dioxatricyclo-(4,3,1,0,3|7)decane of the formula I a in whichR1 is alkoxy of 1 to 4 carbon atoms or benzyloxy, R2 is hydrogen,chlorine, bromine, iodine or -SCN, R3 is hydrogen or acetyl, and the10,11-doublc bond may also be hydrogenated.

1 1 1 2 3. The compound of claim 1, which is S-methoxy-4- ReferencesCited hydfOXy3,10dmethyl 2,9 dioxatricyclo-(4,3,1,0,3q) II deca of theformula I a 3,442,864 s/1969 Magee 26o- 340.3 x

5 NICHOLAS S. RIZZO, Primary Examiner I. H. TURNIPSEED, AssistantExaminer U.S. Cl. X.R.

